Gary L. Goldberg

Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma.

PURPOSE Based on the results of our phase I study that demonstrated the antitumor activity of taxol in a previously treated patient with ovarian cancer, a phase II study was conducted to evaluate the efficacy of taxol in patients with metastatic ovarian cancer and to evaluate further the toxicity of taxol in this group of patients. PATIENTS AND METHODS Thirty-four patients with metastatic ovarian cancer received taxol (180 to 250 mg/m2) as a 24-hour continuous infusion. A premedication regimen was used to reduce the likelihood of an acute hypersensitivity reaction. RESULTS Six of 30 assessable patients demonstrated complete responses (one patient) or partial responses (five patients; 20%; 95% confidence interval [CI], 6% to 34%; range, 2 to 30 months). Additionally, one patient had a less than partial objective response (2 months), and two patients had stable disease for 6 and 15 months. Those responders had a median survival of 27 months, and the nonresponders had a median survival of 6 months (P = .0001). Myelosuppression was the most significant toxicity. Other adverse effects included alopecia and peripheral neuropathy. CONCLUSION Taxol has significant activity in ovarian cancer and should be studied in combination with other active agents earlier in this disease.

Metformin use and endometrial cancer survival

OBJECTIVE Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancers using metformin has been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). METHODS We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. RESULTS Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio=0.54, 95% CI: 0.30-0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and the presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. CONCLUSION Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC.

Expanding the Roles for Pregnane X Receptor in Cancer: Proliferation and Drug Resistance in Ovarian Cancer

Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand. Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western blot. Human ovarian cancer tissue was also analyzed for PXR expression by immunochemistry. Ligand (agonist)–induced PXR target genes were analyzed in SKOV-3 cells by quantitative reverse transcription-PCR. SKOV-3 cell proliferation was assessed by MTT assay. In vivo confirmation of in vitro effects of PXR ligands were done in NOD.SCID mice carrying SKOV-3 xenografts. Results: PXR is expressed in ovarian cancer cells. In SKOV-3 cells, PXR is functional and its activation by cognate ligands induces PXR target genes (CYP2B6, CYP3A4, and UGT1A1) but not MDR1 and MRP2. PXR activation in SKOV-3 cells induces cell proliferation and drug resistance. In mice harboring SKOV-3 xenografts, rifampicin (PXR agonist) induces cell proliferation and tumor growth. Conclusion: PXR activation, regardless of the type of ligand agonist present, promotes the “malignant” phenotype of cancer cells. These data serve as the basis for finding novel nontoxic inhibitors of PXR activation as a method to control cell growth and prevent induction of drug resistance.

Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: Implications for therapy

Abstract There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.

Potentiation of taxol efficacy and by discodermolide in ovarian carcinoma xenograft-bearing mice

Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma. Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects. Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone. Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.

Virulence of papillary endometrial carcinoma

While uterine papillary serous carcinoma (UPSC) has been well described as a virulent subtype of endometrial adenocarcinoma (AC), with behavior similar to that of papillary serous ovarian carcinoma, the papillary endometrial (PE) variant has not been well characterized. We studied 117 patients with endometrial carcinoma identified by our tumor registry, pathology files, and practice records from March 1981 to February 1989: 76 with AC, 26 with PE, and 15 with UPSC. Age and demographic data were similar for all three groups. All of the AC patients, 84% of PE patients, and 87% of UPSC patients had early-stage disease by clinical exam; however, 10% of AC patients, 23% of PE patients, and 87% of UPSC patients had extrauterine disease at surgery (P less than 0.05). Deep myometrial invasion occurred in 29% of AC patients, 36% of PE patients, and 60% of UPSC patients (P less than 0.05). Comparative analysis of the PE and UPSC groups revealed more marked nuclear anaplasia (P less than 0.05) and more frequent vascular space involvement (nonsignificant) in the UPSC group. At 3 years, 75% of the AC group was alive without disease. In contrast, the median progression-free interval for the PE group was 33 months, and for the UPSC group, 9 months (P less than 0.05). These data suggest a transition of increasing virulence corresponding with increasing papillary features, from AC to PE to UPSC. The papillary feature may be a new, significant risk factor in endometrial carcinoma.

Insulin-like Growth Factor 2 Expression Modulates Taxol Resistance and Is a Candidate Biomarker for Reduced Disease-Free Survival in Ovarian Cancer

Purpose: This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. Experimental Design: The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the χ2 or Fishers exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Results: Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05). Conclusions: IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance. Clin Cancer Res; 16(11); 2999–3010. ©2010 AACR.

Ovarian carcinoma of low malignant potential, infertility, and induction of ovulation—Is there a link?

Three cases of ovarian carcinoma of low malignant potential associated with infertility and ovulation induction are reported. The natural history of ovarian epithelial tumors is possibly being interrupted with earlier intervention and diagnosis in patients who may have presented 10 to 15 years later with disseminated ovarian carcinoma.

Altered expression of transforming growth factor‐β1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix

Transforming growth factor‐β1 (TGF‐β1) is a potent growth inhibitor of epithelial cell growth, but can also stimulate stromal cell growth. Loss of responsiveness to TGF‐β1 or loss of TGF‐β1 itself may be important in the progression of cervical intraepithelial neoplasia (CIN) to invasive cervical carcinoma.

Concomitant cisplatin and radiotherapy in locally advanced cervical carcinoma

Patients with locally advanced cervical cancer have a poor prognosis. The efficacy of radiotherapy is limited by the presence of large tumor volume and nodal disease. As cisplatin is a documented radiosensitizer and has activity in squamous cell carcinomas, a prospective study was designed to evaluate the toxicity and potential synergism of concurrent cisplatin (20 mg/m2 x 5 d every 21 days) and radiotherapy in locally advanced cervical cancer. Forty-three patients were studied, of which 14 were stage IB/IIA (bulky disease) and 29 were stage IIB/IIIB/IVA. Of the 32 evaluable patients, there were 29 complete responders. Of these 29 patients, 27 remain without evidence of disease, with a median follow-up of 12 months. There were no treatment-related deaths. Cisplatin and radiotherapy appear to be a well-tolerated and highly effective regimen for locally advanced cervical cancer.